Attention deficit hyperactivity disorder (hereinafter, referred to as ‘ADHD’) is a widely known mental disease showing attention deficit, hyperactivity, impulsivity, etc. This disease has high prevalence in about 5% of school children all over the world, whom have ADHD related symptoms. According to the study of Leibson, et al. (2001, JAMA, 285, 60-66.), a household with a child having ADHD symptom spends about twice as much or more on healthcare than that of the other households without ADHD children. In addition, parents of ADHD children generally suffer from stress, excruciation and, even hypochondriac symptoms, etc.; therefore, a need for ADHD treatment is being highlighted throughout the society. Owing to such high prevalence and influence thereof upon the society, global researches on identification of a pathological mechanism for ADHD have been conducted.
More particularly, in order to stipulate the ADHD mechanism, a number of hypotheses have been proposed and, among these, a dopamine hypothesis is receiving the most attention. However, genome-wide linkage or association studies demonstrated that various genes unrelated to dopamine are associated with ADHD. In addition, specific properties and high geneticity of ADHD strongly suggest existence of various ADHD-related genes.
Meanwhile, the histamine H3 receptor antagonist has functional effects in relation to a wide range of diseases including ADHD, obesity, epilepsy, psychosis, hypochondria, pain, drug abuse/toxicity, and so forth. Furthermore a number of novel compounds are being produced for the treatment of ADHD, cognitive disorders (e.g., Alzheimer's disease), sleep disorders and/or psychosis.
In addition to development of numerous compounds, a variety of ADHD animal models for ADHD studies have been proposed. For instance, Wultz, et al. (Behavioral and Neural Biology, 1990, 53(1), 88-102.) disclosed that existing spontaneous hypertensive rat (hereinafter, referred to ‘SHR’) may be utilized as an ADHD model animal and are now practically used in some ADHD-related studies. In particular, a problem in secretion and metabolism of dopamine in SHR has been found (Russell, et al., Behav. Brain. Res., 1998, 163-171.), which was a significant result in order to demonstrate an important role of dopamine in ADHD. However, noticeable study results demonstrating pathogenic causes of ADHD-associated symptoms of SHR were not reported. Although correlation of dopamine with ADHD is continuously found, a relationship therebetween has yet to be clearly demonstrated. Gainetdinov, et al. (Science, 1999, 283(5400), 397-401.) has proposed a novel ADHD model animal through experimentation using mice with gene deletion of a dopamine transporter (DAT-KO mice). The above article directly demonstrates that a protein relating to the uptake of dopamine is related to ADHD, which is a new discovery to support existing dopamine hypothesis. However, DAT-KO mice also show study results conflicting with the dopamine hypothesis, for example, importance of serotonin rather than dopamine in recovery of ADHD symptoms.
Hess, et al. (J Neurosci., 1992, 12(7), 2865-74.) have taken notice of hyperactivity in mutant mice having partially deleted chromosome 2, Coloboma (hereinafter, referred to as ‘Coloboma’). Afterward, it was found from gene linkage studies that a protein named SNAP-25 present in the deleted chromosome 2 is associated with ADHD. However, further studies on ADHD mechanism of Coloboma mice are now at a standstill since research of the basic origin of ADHD has not been attempted.
Other than the ADHD model animal described above, various models have been proposed. However, they did not show ADHD relating genes or were limited to studies in an animal behavior experimentation level. Therefore, demands for approaches in aspects of molecular biology, cellular biology and/or electric physiology have become conspicuous in order to identify basic origins of ADHD. ADHD study results obtained through such approaches may impart a broader view of the basic origins of ADHD and, in addition, make it possible to discover and/or propose novel medicines. Among existing ADHD medicines, amphetamine and methylphenidate classified as a nerve stimulator are known. According to reports by Swanson, et al. (Neuropsychol. Rev., 2007, 17, 39-59.), precaution of the nerve stimulator to treat ADHD is continuously increased since 1990.
However, such nerve stimulator may derive significant side effects such as hallucination and anxiety. The report by Fleckenstein, et al. (Annu. Rev. Pharmacol. Toxicol., 2007, 47, 681-698.) suggested that a nerve stimulator may damage dopamine secreting nerve cells and/or serotonin secreting nerve cells; Kolb et al. (Proc. Natl. Acad. Sci. USA, 2003, 100, 10523-10528.) disclosed a research result wherein continuous dose of amphetamine may influence structural plasticity of nerve cells, in turn restricting learning and memory performance through new experiences. Such side effects, neuro-cellular toxicity and adverse influence of the nerve stimulator upon memory and learning performance may raise a requirement for novel ADHD medicines.
G protein-coupled receptor kinase interacting protein 1 (hereinafter, referred to as ‘GIT1’) is a multi-functional adaptor protein and comprises several domains including, for example, GTPase-activating domain for ARF small GTPases (ARF GAP domain). The ARF GAP domain of GIT1 has an important role in transporting beta 2-adrenaline receptor and other G-protein combined receptor through phagocytosis. In addition, GIT1 combines with a variety of signal transfer proteins such as GRK, PIX, FAK, PLCγ, MEK1, Piccolo, liprin-α, paxillin, etc., as well as adaptor proteins, thus meaning that GIT1 can function as a signal transfer adaptor.
GIT1 in the brain is substantially present in synapse, and participates in growth of axons, formation of dendritic spine-structure, synapse formation, localization of synapse AMPA [2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propanoic acid] receptor (referred to as ‘AMPA receptor localization’), and so forth. GIT1 combines with a Huntington protein associated with Huntington's disease and a research result of observing a division of GIT1 protein in the brain of a patient suffering from Huntington's disease has been reported. Further, another research result obtained using GIT1 knock-out mice demonstrated growth of dendrites, decrease in density of dendritic spines, and deterioration in learning and memory performance (Prashanthi Menon, et al., Brain Res. 2010; 1317: 218226), thereby suggesting that GIT1 is in a charge of significant functions in the brain.
However, current GIT1 studies are limited to molecular biological and cellular biological applications, and behavior experimentations in the related art have substantially not proposed a correct mechanism sufficiently explaining and/or supporting results of the experimentations.
The present inventors have executed experimentations such as electroencephalogram (hereinafter, referred to as ‘EEG’) measurement in a system level, using GIT1 knock-out mice as an ADHD model animal, in addition to existing methods based on molecular biology, cellular biology and animal behavior research, in order to provide genetic causes of basic origins for ADHD. Further, there is also provided a screening method of a novel ADHD medicine using GIT1 knock-out mice showing ADHD symptoms.